Borrelia burgdorferi causes persistent mammalian infection despite the development of strong immune responses to the pathogen. To avoid immune clearance, B. burgdorferi must evolve immune evasion strategies. One well-characterized strategy is VIsE antigenic variation. They have hypothesized two additional mechanisms that B. burgdorferi potentially uses to escape immune clearance: (1) to down regulate surface-exposed and antibody-targeted lipoproteins, and (2) to gain host components and protect itself. They have made progress toward addressing the first hypothesis. Through an analysis of expression of 137 putative lipoprotein genes on the course of murine infection, they have identified a two-step molecular adaptation process by B. burgdorferi. For the first step, regardless whether the initial inocula of B. burgdorferi express either all of or less than 40 of the 137 lipoprotein genes, the spirochetes are modulated to transcribe 116 of the genes within 10 days post-infection. During the second step, which occurs between 17 and 30 days post-infection, immune selection pressure forces B. burgdorferi to down-regulate most have, but expresses 33 of the 116 genes. This adaptation process could be a critical step for B. burgdorferi to proceed to chronic infection since the pathogen would be cleared at the early stage of infection if the spirochete failed to undergo the process. Immune selection pressure consists of humoral and cellular immune responses. In this project, they will dissect the influence of both responses on B. burgdorferi adaptation using B-cell-deficient mice and T-cell-deficient mice. To fully explore the hypothesis, they will also examine the influence of immune selection pressure on B. burgdorferi adaptation in the tick vector, and the influence of specific antibodies to individual lipoproteins on gene expression in the murine host. Although most of B. burgdorferi lipoprotein genes are down regulated, all known ligand-binding lipoproteins are persistently expressed during chronic infection, including decorin-binding proteins A and B, fibronectin-binding protein, and Erp proteins. This is the basis for the second hypothesis that B. bufgdorfer gains host components and protects itself from immune clearance. In this project, they will also examine this hypothesis using decorin-deficient mice.